The starting materials for the methods of the present invention are seven membered cyclic ureas containing C-2 symmetry. They have biological activity as human immunodeficiency virus (HIV) protease inhibitors. The asymmetric N,N'-disubstituted cyclic urea products of the methods of the present invention have also exhibited biological activity as human immunodeficiency virus (HIV) protease inhibitors for the treatment of HIV infection.
Debenzylation by the use of metals in liquid ammonia has been demonstrated on various substrates. The removal of O-benzyl protecting groups has been shown by Weinreb et al., J. Org. Chem., 46, 5383 (1981), while removal of benzylated amides is reported in the following references: Hecht and Ohgi, J. Org. Chem., 46, 1232 (1981); and Silverstein et al., Tetrahedron Lett., 27, 4941 (1986). These disclosures however do not address the selective removal of a single benzyl protecting group from bisbenzylated substrates.
The monodebenzylation of N,N'-disubstituted cyclic ureas can be found in the synthesis of biotin reported by Field, J. Org. Chem., 43, 1084 (1978), and Goldberg and Sternbach, U.S. Pat. Nos. 2,489,232 and 2,489,235 (issued Nov. 22, 1949). These references report removal of one N-benzyl protecting group from a bisbenzylated asymmetric cyclic urea with the stoichiometric use of sodium in liquid ammonia. The references teach that the debenzylation is governed by the alleviation of steric strain within the molecule. A method requiring a strict titration to a visual endpoint is described. The addition of the alkali metal to the solution containing the substrate in portions is used to achieve the desired amount of alkali metal. This approach requires the delicate addition of sodium and stipulates the use of precisely two equivalents of sodium. The only phenyl groups present in the biotin synthesis are those of the two N-benzyl protecting groups and under the conditions reported, overreduction was not a significant concern.
The process described herein involves symmetrical starting materials from which clean monodebenzylation would not be predicted. The selectivity cannot be attributed to alleviation of steric strain as in asymmetrical molecules. Additionally, the compounds of the present invention contain several benzyl groups present on carbon as well as nitrogen atoms wherein Birch reduction of the additional aromatic rings would be expected.
It was not previously appreciated that the amount of metal used is critical to obtaining a clean monodebenzylation product uncontaminated by starting material or completely debenzylated material. The present invention finds utility in the discovery that the use of excess sodium is not only permissable, but necessary for this class of compounds. This allows for the reverse addition of the substrate to the sodium ammonia mixture, eliminating the need for an undesirable titration with sodium on a large scale.
The order of addition described herein is desirable for large scale processes. The method calls for less handling of potentially harmful reactants because there is no need to accurately distribute elemental sodium. The substrate can be predissolved in a wide variety of co-solvents when the solubility in ammonia is low, and the reaction rate can easily be controlled by the flow rate of the addition solution which could prove critical considering the exothermic nature of the reaction.
Despite the conditions reported in the literature, the methods previously described are unattractive for a scalable process. There remains a need for a safe, viable and efficient process for the selective removal of benzyl protecting groups from symmetrical intermediates. These compounds can then be alkylated to give a wide range of unsymmetrical products which are useful as HIV protease inhibitors for the treatment of HIV infection.